Genome-wide analysis of Structural Variants in Parkinson's Disease using Short-Read Sequencing data

Billingsley, K. J.; Ding, J.; jerez, p. a.; illarionova, a.; Makarious, M. B.; moore, a.; vitale, d.; reed, x.; Hernandez, D.; Torkamani, A.; Ryten, M.; Hardy, J.; Chia, R.; Scholz, S. W.; Traynor, B.; Dalgard, C. L.; ehrlich, d.; Tanaka, T.; Ferrucci, L.; Beach, T.; Serrano, G. E.; Quinn, J.; Bubb, V.; Collins, R. L.; Zhao, X.; Walker, M.; Pierce-Hoffman, E.; Brand, H.; Talkowski, M.; Casey, B.; Cookson, M. R.; Markham, A.; Nalls, M. A.; Mahmoud, M.; Sedlazeck, F.; Blauwendraat, C.; Gibbs, R.; Singleton, A.

doi:10.1101/2022.08.22.504867

Home/Archive/bioRxiv

bioRxiv · 10.1101/2022.08.22.504867

Genome-wide analysis of Structural Variants in Parkinson's Disease using Short-Read Sequencing data

View original source ↗Export metadata ↓

Abstract

Parkinsons disease is a complex neurodegenerative disorder, affecting approximately one million individuals in the USA alone. A significant proportion of risk for Parkinsons disease is driven by genetics. Despite this, the majority of the common genetic variation that contributes to disease risk is unknown, in-part because previous genetic studies have focussed solely on the contribution of single nucleotide variants. Structural variants represent a significant source of genetic variation in the human genome. However, because assay of this variability is challenging, structural variants have not been cataloged on a genome-wide scale, and their contribution to the risk of Parkinsons disease remains unknown. In this study, we 1) leveraged the GATK-SV pipeline to detect and genotype structural variants in 7,772 short-read sequencing data and 2) generated a subset of matched whole-genome Oxford Nanopore Technologies long-read sequencing data from the PPMI cohort to allow for comprehensive structural variant confirmation. We detected, genotyped, and tested 3,154 "high-confidence" common structural variant loci, representing over 412 million nucleotides of non-reference genetic variation. Using the long-read sequencing data, we validated three structural variants that may drive the association signals at known Parkinsons disease risk loci, including a 2kb intronic deletion within the gene LRRN4. Further, we confirm that the majority of structural variants in the human genome cannot be detected using short-read sequencing alone, encompassing on average around 4 million nucleotides of inaccessible sequence per genome. Therefore, although these data provide the most comprehensive survey of the contribution of structural variants to the genetic risk of Parkinsons disease to date, this study highlights the need for large-scale long-read datasets to fully elucidate the role of structural variants in Parkinsons disease.

Explore related subjects

genetics Preprint

Keep this discovery

Explore connections, maps & timelines

BibTeX RIS

Billingsley, K. J., Ding, J., jerez, p. a., illarionova, a., Makarious, M. B., moore, a., vitale, d., reed, x., Hernandez, D., Torkamani, A., Ryten, M., Hardy, J., Chia, R., Scholz, S. W., Traynor, B., Dalgard, C. L., ehrlich, d., Tanaka, T., Ferrucci, L., Beach, T., Serrano, G. E., Quinn, J., Bubb, V., Collins, R. L., Zhao, X., Walker, M., Pierce-Hoffman, E., Brand, H., Talkowski, M., Casey, B., Cookson, M. R., Markham, A., Nalls, M. A., Mahmoud, M., Sedlazeck, F., Blauwendraat, C., Gibbs, R., Singleton, A.. 2022-08-22. Genome-wide analysis of Structural Variants in Parkinson's Disease using Short-Read Sequencing data. https://doi.org/10.1101/2022.08.22.504867

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

Host control and regulation of human anellovirus persistence

Anelloviruses are the most abundant and diverse eukaryotic viruses known to infect humans and can persist throughout our lifetimes. Despite their ubiquity, the host factors governing their physiologic distribution and abundance remain poorly understood. Here, we construct a viral pangenome of 2,023 strains to quantify anellovirus DNA in >1.1 million participants spanning three genetic biobanks. Genome-wide association studies identify 121 loci linked to viral persistence, predominantly via immune regulation by NF-kB signaling. Further, we associate variable anellovirus detection with conditions characterized by immune dysfunction, including lymphoid malignancies. By screening 3.2 petabases of human single-cell sequencing data, we identify myeloid progenitors in the bone marrow as a prominent site of anellovirus transcription in vivo. Finally, Perturb-seq of anellovirus proteins reveals that anellovirus ORF2, particularly from Alphatorquevirus, attenuates TNF-a-induced NF-kB signaling, connecting host genetic variation, cellular context, and viral immunomodulation to characterize the persistence of the eukaryotic human virome's most abundant component.

genetics↗

bioRxiv2026

SARDINE unlocks EWAS summary statistics for large-scale epigenetic biomarker analysis

Epigenetic clocks are increasingly used to study biological aging, yet their interpretation and utility remain uncertain. Meanwhile, the growing wealth of epigenome-wide association study (EWAS) summary statistics remains largely untapped for evaluating these biomarkers. Here, we introduce SARDINE, a statistical framework that estimates epigenetic clock-phenotype associations using EWAS summary statistics, clock weights, and reference methylation covariance, without individual-level data. SARDINE accurately reproduced individual-level association estimates across 38 epigenetic biomarkers and four phenotypes in 15,677 individuals. Applying SARDINE to diverse EWAS datasets revealed substantial heterogeneity in biomarker associations with aging, diseases, and lifestyle factors. By transforming CpG-level EWAS results into interpretable biomarker-level associations, SARDINE unlocks a largely underutilized data resource and establishes a scalable paradigm for systematic biomarker evaluation and discovery in aging research.

genetics↗

bioRxiv2026

Deep transcriptomic analysis of molecular mediators of complex traits in heterogeneous stock (HS) rats

Rats are a powerful model organism for genome-wide association studies (GWAS) of physiological and behavioral traits. Heterogeneous Stock (HS) rats, which were created by intercrossing 8 inbred rat strains, are heavily used for this purpose because of their genetic diversity and accumulated recombinations due to over 100 generations of outbreeding, which improves mapping precision. However, functional genomics resources for post-GWAS interpretation of genomic findings have been limited. We processed 3,160 RNA-seq samples, 1,932 of which were previously unpublished, from 13 tissues as part of RatGTEx. We used Pantry to quantify six modalities of transcriptome regulation (expression, isoform ratio, intron excision ratio, alternative transcription start site (TSS), alternative poly(A), and RNA stability) in each sample, which allowed us to identify 144,876 independent quantitative trait loci (QTL) for 22,599 genes. We performed a transcriptome-wide association study (TWAS) with 19,796 unique genes across tissues and transcriptional modalities and 308 traits collected from 14 studies using FUSION, which identified 7,473 significant gene-trait associations. This work presents a significant expansion of the RatGTEx resource in terms of samples, modes of transcriptome regulation, and genetic analyses. Our findings provide molecular evidence for the involvement of specific genes in mediating GWAS signals through a range of transcriptome regulatory mechanisms. These gene-to-phenotype relationships can be easily applied to genetic analyses in humans and other species. Further experiments can use this evidence to confirm these molecular mediators and target them for the treatment of behavioral and physiological traits and disorders. To facilitate use of these results, we have updated results on RatGTEx.org and provided a new interactive TWAS web portal (twas.ratgtex.org).

genetics↗